Combination antiretroviral therapy has provided many HIV-infected individuals with a near-normal life expectancy, provided they have access to care and can maintain strict lifetime adherence to the daily or more frequent treatment regimens. The most important factor in the virologic failure of an antiretroviral regimen is poor adherence of the patient to complete and proper dosing. HIV-infected IDUs face well-documented challenges to maintaining optimal adherence. Accordingly, this group, which represents approximately one- quarter of the U.S. HIV epidemic, has yet to derive the full benefits of the available antiretroviral therapies. Various interventions to improve antiretroviral drug adherence, ranging from counseling to directly-observed therapy and other structural interventions, have had only modest success. We propose a novel treatment strategy involving systemic administration of long-acting antiretroviral therapy as a means to ensure effective drug delivery and viral suppression in HIV-infected populations prone to poor drug-adherence. We propose a randomized, double-blind, placebo-controlled study of weekly subcutaneous treatment with the CCR5 monoclonal antibody PRO 140 in combination with a standard-of-care oral antiretroviral regimen. PRO 140 is uniquely suited for this use as it is the only HIV drug to demonstrate long-acting viral suppression without the need for slow IV infusion. Success in this pilot study would identify a new strategy for improving the care of HIV-infected IDUs and other vulnerable populations that are underserved by the current generation of antiretroviral medications. Positive results could catalyze this field and spur development and testing of other long-acting HIV drugs in this population.